Reactivators carboxylesterase

Thioesters play a paramount biochemical role in the metabolism of fatty acids and lipids. Indeed, fatty acyl-coenzyme A thioesters are pivotal in fatty acid anabolism and catabolism, in protein acylation, and in the synthesis of triacylglycerols, phospholipids and cholesterol esters [145], It is in these reactions that the peculiar reactivity of thioesters is of such significance. Many hydrolases, and mainly mitochondrial thiolester hydrolases (EC 3.1.2), are able to cleave thioesters. In addition, cholinesterases and carboxylesterases show some activity, but this is not a constant property of these enzymes since, for example, carboxylesterases from human monocytes were found to be inactive toward some endogenous thioesters [35] [146], In contrast, allococaine benzoyl thioester was found to be a good substrate of pig liver esterase, human and mouse butyrylcholinesterase, and mouse acetylcholinesterase [147],... 

A number of prodrugs in clinical use are esters of fatty acids. For example, haloperidol decanoate is of interest in slow-release preparations. This compound was hydrolyzed by such hydrolases as purified carboxylesterase but was reported to be stable in human blood or plasma and in a variety of rat tissue homogenates [107], The source of this apparent lack of reactivity was competitive binding to blood and tissue proteins. In other words, protein binding sequesters this very lipophilic prodrug and prevents enzymatic hydrolysis, thereby slowing its activation and prolonging its in vivo effects. 

Trifluoroacetylchloride is very reactive, and therefore, if any of it escapes from the vicinity of the cytochromes P-450 in the smooth endoplasmic reticulum, it might be expected to react with those proteins in highest concentration. The 59-kDa polypeptide, a microsomal carboxylesterase, constitutes 1.5% of the total microsomal protein, and therefore it fulfils this... 

The inhibition by other organophosphate compounds of the carboxylesterase which hydrolyzes malathion is a further example of xenobiotic interaction resulting from irreversible inhibition because, in this case, the enzyme is phosphorylated by the inhibitor. A second type of inhibition involving organophosphorus insecticides involves those containing the P=S moiety. During CYP activation to the esterase-inhibiting oxon, reactive sulfur is released that inhibits CYP isoforms by an irreversible interaction with the heme iron. As a result, these chemicals are inhibitors of the metabolism of other xenobiotics, such as carbaryl and fipronil, and are potent inhibitors of the metabolism of steroid hormones such as testosterone and estradiol. 

Maxwell, D.M., Brecht, K.M. (2001). Carboxylesterase specificity and spontaneous reactivation of an endogenous scavenger for organophosphate compounds. J. Appl. Toxicol. 21 S103-S107. 

Sterri, S.H., Fonnum, F. (1987). Carboxylesterases in guinea-pig plasma and liver tissue specific reactivation by diacetylmonoxime after soman inhibition in vitro. Biochem. Pharmacol. 36 3937-42. 

Zhong G, Lemer RA, Barbas CF 111. Broadening the aldolase catalytic antibody repertoire by combining reactive immunization and transition state theory new enantio- and diastereoselectivi-ties. Angew. Chem. Int. Ed. Engl. 1999 38(24) 3738-3741. Schowen RL. The elicitation of carboxylesterase activity in antibodies by reactive immunization with labile organophos-phorus antigens a role for flexibility. J. Immunol. Methods 2002 269(l-2) 59-65. 

Mechanism of interaction of A- and B-esterases with OPC is similar. B-esterases initially form Michaelis complex with an OPC inhibitor producing phosphorylated or inhibited enzyme that either reactivates very slowly or does not reactivate at all (Figure 3) [1], However, after forming Michaelis complex with OPC A-esterases perform intensive and permanent hydrolysis of OPC and their catalytic activity and turnover rate are very high. It was already shown that carboxylesterases, as a typical B-esterase, can hydrolyze carboxylic esters that serve as functional groups in OPC such as malathion thus performing detoxication of the compound [26, 27]. 

Maxwell, D.M., Lieske, C.N., and Brecht, K.M., Oxime-induced reactivation of carboxylesterase inhibited by organophosphoms compounds, Chem. Res. Toxicol., 7,428, 1994. 

Mo.st OP pesticides react preferentially with BuChE. In contrast, most OP nerve agents react preferentially with AChE. Carboxylesterase is also highly reactive with most OPs. This complicate.s the comparison of studies on rodents with studie,s on monkeys and humans because rodenhs have very high concentrations of carboxylesterase in plasma, whereas monkeys and humans have no carboxylesterase in plasma. On the other hand, albumin has esterase activity (Means and Wu, 1979), and this is sometimes mistaken for carboxylesterase activity in human plasma. 

Certain oximes, such as bispyridinium oxime HI 6 and 2-PAM, have been reported to protect against soman toxicity. Pretreatment with HI 6 (50 mg/kg) together with atropine (10 mg/kg) increased the LC50 (LC50 X time) in rats by a factor of 7 (Schoene et al. 1985). HI 6 is an effective reactivator of soman-inhibited acetylcholinesterase. Its protective action was found to be greater in mice than in guinea pigs (Maxwell and Koplovitz 1990). In addition to reactivation of the enzyme acetylcholinesterase inhibited by soman, HI 6 produced an effect on carboxylesterase that... 

The methods for determination of blood cholinesterases inhibition (AChE and BuChE) do not allow identification of the OP and do not provide reliable evidence for exposure at inhibition levels less than 20%. Moreover, they are less suitable for retrospective detection of exposure due to de novo synthesis of enzymes. A method has been developed which is based on reactivation of phosphylated cholinesterase and carboxylesterase (CaE) by fluoride ions. Treatment of the inhibited enzyme with fluoride ions can inverse the inhibition reaction, yielding a restored enzyme and a phos-phofluoridate which is subsequently isolated and quantified by gas chromatography and phosphorus-specific or mass spectrometric detection (Dll, Pll). Human (and monkey) plasma does not contain CaE but its BuChE concentration is relatively high [70-80 nM (M25, D8)], much higher than the concentration of AChE in blood [ca. 3 nM (H5)]. The plasma of laboratory animals, such as rats and guinea pigs, contains considerable concentrations... 

Estevez, Garcia-Perez, A., Barril, et al., 2011. Inhibition with spontaneous reactivation of carboxylesterases by organophosphorus compounds para-oxon as a model. Chem. Res. Toxicol. 24, 135-143. 

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